gsk3β介导了内质网应激诱导tau蛋白过度磷酸化及大鼠空间记忆障碍-gsk 3β mediated endoplasmic reticulum stress-induced hyperphosphorylation of tau protein and spatial memory disorder in rats.docx

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gsk3β介导了内质网应激诱导tau蛋白过度磷酸化及大鼠空间记忆障碍-gsk 3β mediated endoplasmic reticulum stress-induced hyperphosphorylation of tau protein and spatial memory disorder in rats.docx

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gsk3β介导了内质网应激诱导tau蛋白过度磷酸化及大鼠空间记忆障碍-gsk 3β mediated endoplasmic reticulum stress-induced hyperphosphorylation of tau protein and spatial memory disorder in rats

制。细胞水平，用thapsigargin处理HEK293/tau细胞，以及同时联合给予不同浓度的SB216763或转染dnGSK-3β(dominant-negativeGSK-3β)质粒，利用免疫印迹技术检测tau蛋白的磷酸化水平及其机制。结果：在本实验中我们观察到以下结果。⑴Tunicamycin/thapsigargin诱导内质网应激。⑵内质网应激导致大鼠空间记忆障碍、tau蛋白的过度磷酸化以及GSK-3β的激活。⑶抑制GSK-3β，可以改善内质网应激所诱导的大鼠空间记忆障碍及tau蛋白的过度磷酸化。⑷内质网应激通过Akt,Fyn和PTP1B介导的途径，激活GSK-3β。⑸内质网应激发生时，静息状态下与内质网跨膜蛋白PERK、IRE-1、ATF-6结合的内质网陪伴分子Bip游离下来，通过与GSK-3β、tau蛋白的结合，导致tau蛋白的过度磷酸化。由此我们得出以下结论：内质网应激通过Akt、Fyn和PTP1B途径激活GSK-3β，从而诱导tau蛋白过度磷酸化及其大鼠空间记忆障碍。关键词:内质网应激，tau蛋白磷酸化，空间记忆，糖原合成激酶-3β，阿尔茨海默病EndoplasmicreticulumstressinducestauhyperphosphorylationandspatialmemorydeficitsbyactivatingGSK-3βAbstractBackground:Endoplasmicreticulum(ER)stresshasbeenindicatedinvolvedinthepathologicalprocessofAlzheimer’sdisease(AD),buttheunderlyingmechanismswerestillpartiallyunderstood.HyperphosphorylatedtauplayscrucialroleinthedevelopmentofADpathologiesandthecognitiveimpairments.Inaddition,glycogensynthasekinase-3β(GSK-3β),oneofthemostimplicatedtaukinasesinvolvedinAlzheimer-liketauhyperphosphorylationhasbeendemonstratedtobeactivatedbyERstress.Therefore,therelationamongERstress,tauphosphorylationandGSK-3βwasinvestigatedinthisstudy.Objective:TostudytheinfluenceofERstressonspatialmemoryinratsandtauhyperphosphorylationinvivoandvitro,andtheunderlyingmechanism.Methods:Invivo,weinjectedtunicamycinorthapsigarginintotheratbrainventricletoinduceERstress,SB216763wassimultaneouslyinjectedtoinhibitactivitiesofGSK-3β.Invitro,weusedthapsigargintotreatHEK293/taucellsandGSK-3βinhibitor（SB216763）wassimultaneouslyco-incubated.Spatialmemoryretentionofrats,tauphosphorylationandactivitiesofGSK-3βweredetectedbyWesternblotting,immunoprecipitationandMorriswatermaze.Results:⑴Invivo,tunicamycinandthapsigargininducesERstress.⑵ERstressinducestauhyperphosphorylationandspatialmemorydeficitsinratswithactivationofGSK-3β.⑶InhibitionofGSK-3βarrestsERstress-inducedtauhyperphosphorylationandimprovesthespatialmemoryoftherats.⑷ActivationofGSK-3βbyERstressinvolvesAkt-,Fyn-andPTP1B-mediatedpathways.⑸TheincreasedBipinducedbyERstressenhanc